In patients with UC, CD103 DCs show the impaired ability to generate Treg cells, but exhibit a colitogenic function inducing Th1/Th2/Th17 responses. These findings show how human CD103 DCs could contribute to the pathogenesis of UC.

No abstract

OBJECTIVES: Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6–induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. METHODS: We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. RESULTS: UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). DISCUSSION: Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.

T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4 + tissue-resident memory T cell (Trm) subset that is increased in Crohn’s disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4 + Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4 + Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4 + Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4 + T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Crohn's disease causes chronic inflammation in the gastrointestinal tract and its pathogenesis remains unclear. In the intestine of Crohn's disease patients, CD14 + CD11 + CD163 low macrophages contribute to inflammation through the induction of Th17 cells and production of inflammatory cytokines; the CD14 + CD11c + 163 high fraction is anti-inflammatory through the production of IL-10 in normal cases. In this report, the 16S rRNA gene amplicon sequencing method was used to identify bacteria that are specifically present in intestinal CD14 + CD11c + macrophages of crohn's disease patients. Bacteria present in intestinal CD14 + CD11c + macrophages and mucus of crohn's disease patients were separated into different clusters in principal coordinates analysis. There was a statistically significant increase in the relative composition of CD14 + CD11c + macrophages from mucus in two phyla (Proteobacteria [p = 0.01] and Actinobacteria [p = 0.02]) and two families (Moraxellaceae [p < 0.001] and Pseudomonadaceae [p = 0.01]). In addition, OTU-1: Acinetobacter and OTU-8: Pseudomonadaceae tended to concentrate in the CD14 + CD11c + CD163 low subset, whereas OTU-10: Proteus, OTU-15: Collinsella tended to concentrate more in the CD14 + CD11c + CD163 high subset than the other subset and mucus.Crohn's disease causes chronic inflammation in the gastrointestinal tract and is known as inflammatory bowel disease (IBD) together with ulcerative colitis, yet fundamental therapy has not yet been established. Inflammatory reactions are usually controlled in the intestinal tract and intestinal homeostasis is maintained. In IBD, chronic inflammation is thought to occur by maintaining an excessively activated state of immune cells through the involvement of several factors, including genetic factors, environmental factors, immune abnormality, and intestinal bacteria 1,2 .In the intestinal tract of Crohn's disease, CD14 + macrophages are increased compared to normal intestine. CD14 + macrophages are more ability to produce inflammatory cytokines such as IL-23, TNF-α, and IL-6 than CD14 − macrophages 3 . CD14 + macrophages also have the ability to induce Th17 cells, but in the intestines of